In our ongoing research into the leading ocular cause of childhood blindness, retinopathy of prematurity (ROP), we have documented many highly prevalent, clinically significant sequelae that persist long after the preterm ages at which ROP is active. These include short axial length, high myopia, anisometropia and, perhaps most critically, persistent retinal dysfunction. Although these outcomes are common, even in eyes in which the ROP was mild (the vast majority), the mechanisms that cause and link them remain poorly understood. We will examine these mechanisms. Our observations in both human ROP subjects and rat models strongly suggest that abnormalities of the neural retina, of the vasculature, and of refractive development, are biologically related comorbidities, and that retinal neurons, especially rod photoreceptors, instigate the chain of events that results in all these sequelae. Therefore, we will use the oxygen-induced retinopathy 'ROP rat model to test our novel hypothesis that persistent neurovascular dysfunction is the basis of poor ROP outcomes years after active disease has resolved. To facilitate ready translation to our clinical research and patient care, we will make use of complementary, innovative procedures to study the function and structure of the neural retina and its vascular supply, and associations with altered refractive development, in individual, living eyes. Our pioneering approach will permit longitudinal study from vaso-obliteration through active ROP to maturity. This will enable individualized developmental growth curves to be derived and quantitative measures of each feature (vascular, neural, refractive) to be evaluated for their ability to predict outcomes in other features, suggesting cause-and-effect relationships. In cross-sectional tests at the same timepoints, studies of biochemical signaling pathways in subsets of rats will investigate the molecular bases of the shared neural, vascular, and refractive patterning mechanisms. Then, mindful that (1) ROP has its onset at preterm ages when the outer segments of the energy-demanding rods first appear, (2) the severity of rod dysfunction at a young age predicts vascular outcomes but not vice versa, (3) administration of a visual cycle modulator that lowers metabolic demands of rods protects the immature retinal neurons and improves vascular outcomes, (4) neural and vascular development is under cooperative molecular control, (5) the retina is a major controller of eye growth and refractive development, and (6) photoreceptors use less energy in the light because light suppresses the circulating current, we will attempt to beneficially regulate ambient light to the benefit of all these sequelae-vascular, neural, and refractive-using a series of dark and light exposures designed with reference to the developmental course of the photoreceptors. Light regulation is safe, economical, suitable as monotherapy or combination-therapy with other treatments, and applicable even to mild ROP that does not currently qualify for any intervention, and thus readily translatable. The new knowledge generated herein will, we hope, lead to game-changing approaches to understanding and treating-nay, preventing!-the most common sequelae of ROP.